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Appalachia is the general name given to post-apocalyptic West Virginia. Located within the Eastern Commonwealth of the former United States, the region was spared most of the destruction and carnage of the Great War due to its relative isolation and lack of strategic targets, but much of the surviving human population nonetheless perished over the following years due to the Scorched Plague. In 2102, the residents of Vault 76 emerged into Appalachia after twenty-five years of isolation and began to reclaim the wilderness.

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In 2102, twenty-five years after the Great War, Appalachia consists of a vast, mostly intact swathe of the state of West Virginia, and becomes the focus of reconstruction efforts led by the residents of Vault 76.

While the predominately rural landscape is mostly unscathed, it is plagued by irradiated and mutated creatures. Of particular concern is the Scorched Plague, caused by a hazardous, mutagenic fungus indigenous to the vast caverns beneath Appalachia. Scorched plague is spread by scorchbeasts, which periodically breach the surface and terrorize the countryside.